Generally ISFETs were built for continuous time (analogue) measurement with analogue pre-processing circuits around them. Normally analogue to digital conversion is one of the processing steps. This is the case where a continuum of values is needed. However, there are many applications where a yes/no decision is sought. For example, in DNA hybridization and SNP insertion detection, it is enough to detect that a process took place or not with a yes/no answer (5) (6). Other applications require just comparison between concentrations of two chemicals in a solution. For example, if Creatinine is of higher concentration than Urea or vice versa (7).
An Ion Sensitive Field Effective Transistor (ISFET) is comprised of a Field Effective Transistor (FET) whose gate is exposed to ionic charges in a electrolyte. A reference electrode is immersed in the electrolyte solution which comes into contact with the gate oxide of the transistor. See FIG. 1. Therefore, the combination of the electrolyte and the reference electrode plays the role of the gate in a normal MOSFET. The gate oxide becomes the ions sensitive membrane. The electrical operating modes of a FET may be expressed by:
                              Weak          ⁢                                          ⁢          inversion                ⁢                                  ⁢                              I            DS                    =                                    I                              D                ⁢                                                                  ⁢                0                                      ⁢                          W              L                        ⁢                          ⅇ                              (                                                                            V                      Gs                                        -                                          V                      t                                                                            nU                    T                                                  )                                                                                                                  Triode          ⁢                                          ⁢          Region          ⁢                                          ⁢          Saturation                ⁢                                  ⁢                              I            DS                    =                      μ            ⁢                                                  ⁢                          C              ox                        ⁢                          W              L                        ⁢                          (                                                                    (                                                                  V                        gs                                            -                                              V                        t                                                              )                                    ⁢                                      V                    DS                                                  -                                                      V                    DS                    2                                    2                                            )                                      ⁢                                  ⁢                              I            DS                    =                                    1              2                        ⁢            μ            ⁢                                                  ⁢                          C              ox                        ⁢                          W              L                        ⁢                                          (                                                      V                    GS                                    -                                      V                    t                                                  )                            2                        ⁢                          (                              1                +                                  λ                  ⁢                                                                          ⁢                                      V                    DS                                                              )                                                          (        1        )            
The voltage drops arising from interactions of the reference electrode, the electrolyte and the ion sensitive membrane can be viewed as part of either the gate-source voltage (Vgs) or the threshold voltage (Vt). This is supported by the fact that it is their difference that appears in the MOSFET Id−Vgs relations in all regions of operation, equation (1).
From the above analogy, it was debated whether the reference electrode remotely plays the role of the MOS gate (1). Therefore, the electrolyte plays the role of the gate metal which comes into contact with the gate-oxide. In MOSFET, Vt is decided by the gate material, substrate doping, their insulator and the charges in this system, equation (2). It is a constant for each device; and because the manufacturing process is very well controlled, its variation across devices is well controlled. However, in the ISFET according to this analogy, the electrolyte became part of this system making its Vt dependant on the electrolyte properties, equation (3) (1). The threshold voltage may be expressed by:
                              MOSFET          ⁢                                          ⁢                      V            t                          =                                                            Φ                M                            -                              Φ                Si                                      q                    -                                                    Q                ox                            +                              Q                ss                            +                              Q                B                                                    C              ox                                +                      2            ⁢                          ϕ              f                                                          (        2        )                                          ISFET          ⁢                                          ⁢                      V            t                          =                              -            Ψ                    +                      χ            sol                    -                                    Φ              Si                        q                    -                                                    Q                ox                            +                              Q                ss                            +                              Q                B                                                    C              ox                                +                      2            ⁢                          ϕ              f                                                          (        3        )            
Where: φM is the metal work function, φSi is the Silicon work function, q is the electron charge, Qox is accumulated charges in the oxide insulator, Qss is trapped charge in the oxide-Silicon interface, QB is depletion charge in the silicon bulk, Cox is gate oxide capacitance, and φf defines the onset of inversion depending on silicon doping levels. In equation (3), φM is replaced by both the chemical parameter of the ion sensitive membrane-electrolyte interface potential Ψ, and the surface dipole potential of the electrolyte in contact with the ion sensitive membrane χsol. The former is a function of the electrolyte ion concentration, where pH is a possible measure of it. The latter is a constant. Equation (3) suggests that the ISFET's threshold voltage can be modified using electrolyte ion concentration (1).
In 1999, Bausells et al integrated an ISFET using the 1 μm single poly-silicon, double metal standard CMOS process of Atmel-ES2 (10). They integrated a standard CMOS amplifier in the same die. Basically, the ISFET was given, for the first time, a poly-silicon gate that was floating and connected to the metal stack until the topmost metal layer where the ions were sensed through the oxi-nitride passivation. This basic idea was carried out by others and ISFETs were built in different commercial CMOS processes with multiple metal layers (10) (11) (12).
It is interesting to note that the transistor part here is effectively an FG-MOSFET and the sensitive part looks like an ion sensitive capacitor where the topmost metal is one plate and the electrolyte forms the second while passivation is the insulation layer. This is very similar to the traditional capacitive ion sensor which results if the reference electrode is removed.
The passivation capacitance from the transistor's gate may be considered split to make two different structures. Hence, the ISFET's transistor gate may be called the “electrical gate” and the topmost metal under the ion sensitive membrane may be called the “chemical gate”.
Therefore, Vt is a process dependant constant given by equation (2). The chemical dependence introduced into equation (3) may be expressed as part of the floating gate voltage of the ISFET given by:VFC=VrefΨ+χsol+VQpass  (4)
Where, VQpass is due to the trapped charges in the passivation layer.
Using the site-dissociation model and the Gouy-Chapman-Stern double layer model, the ISFET may be modeled as in FIG. 2. Where Vchem is the chemical voltage arising from the electrolyte and its interface to both reference electrode and ion sensing membrane (6).Vchem=γ+VQpass+2.3αUTpH  (5)
Where, γ is a grouping of all pH independent terms apart from passivation trapped charges which is VQpass. UT is the usual thermal voltage, and α is a sensitivity parameter with values between 0<α<1. Its maximum gives the theoretical limit known as the Nernstian sensitivity given by 59.2 mV/pH at 25° C. (1).
Most of the publications about ISFETs consider Vt as the pH dependant parameter. The inventors have appreciated that from a pure circuit point of view, the ISFET is effectively a standard FGMOS with its gate capacitively coupled to the superimposed voltages Vref and Vchem. Therefore, they considered them to form the floating gate input and assume Vt as a constant, like a standard MOSFET. Thus a pH change is can be seen as a modulation for Vgs instead of Vt. However, from a physical point of view, there is no change to the system and the same analysis holds. Therefore, equations (1) and (2) are still valid, equation (3) is no more relevant, and equation (5) represents the chemical voltage.
The first attempt to use an ISFET to build an inverter was by Dr. Shepherd and her colleagues (5) (16). FIG. 4 shows an ISFET as an NMOS in a standard class AB inverting amplifier with the PMOS role taken by a normal transistor. The input is connected to both the gate of the PMOS (M2) and the reference electrode of the n-ISFET (X1). Therefore, the switching threshold of the circuit shifts in proportion to the solution's pH.
Therefore pH changes modulate the gate voltage of the n-MOS but not the p-MOS. That is, only half of the complementary pair is pH sensitive. The pull up transistor sees a different input than the pull down transistor, the difference being Vchem.
However, this may be acceptable if there is no drift or passivation trapped charges. An ISFET's Vt can have an initial variation, due to passivation trapped charges, in the range of few Volts (17) (12). This can render the switching function of that circuit non-operational, especially if the n-ISFET had a negative threshold voltage.